Diabetic retinopathy (DR) is already the leading cause of blindness in working age adults, and the incidence of DR is predicted to double in the US by 2050 (NIH National Eye Institute data). With the prevalence of diabetes in veterans significantly higher than the civilian population, it is imperative that we develop new and more effective treatments for vision loss caused by DR. In the last funding cycle, we identified a novel neuroprotective agent for early stage DR: dopamine. Our research confirmed a dopamine deficiency in retinas of diabetic rodents and showed that treatment with the dopamine precursor, L-DOPA, protects against early functional deficits in DR. The purpose of this proposal is to fill key knowledge gaps about dopamine treatment for DR that are necessary to translate dopamine therapies to the clinic, including whether L-DOPA alters late stage vascular deficits, the efficacy of long-term dopamine receptor agonist treatment, and the lowest beneficial dose. Dopamine is an important neuromodulator in the retina that plays key roles in circadian rhythms, retinal sensitivity under different lighting conditions, and visual function. In addition, loss of dopamine stimulates angiogenesis. Thus, dopamine deficits caused by hyperglycemia may contribute to both neuronal and vascular deficits in DR. Our preliminary results show that L-DOPA treatment in early stages of DR in rodents preserved visual acuity and contrast sensitivity as measured by optokinetic tracking (OKT) and retinal function recorded using electroretinography (ERG). However, the clinical impact of improving neuronal aspects of diabetic eye disease is unknown. Most aspects of vision loss attributed to diabetes are related to vascular pathology through either leakage and/or abnormal proliferation. Thus, it is critical to determine if dopaminergic treatment also affects the vascular pathology through direct or indirect processes. In Aim 1, we will establish the role of dopamine deficiency in neuronal and vascular pathology in DR by testing the hypothesis that L-DOPA treatments will slow or halt early and late stage deficits in DR by protecting both retinal neurons and vasculature. Dopamine diffuses through the retina by volume transmission and binds to dopamine receptors in multiple cells types in the eye. Our preliminary data in diabetic mice show that acute treatment with dopamine D1 and D4 receptor agonists can selectively restore visual acuity and contrast sensitivity, respectively. These results suggest potential contributions of specific dopamine receptors to early visual dysfunction. In addition, a D2 receptor agonist, bromocriptine, is already FDA approved for type 2 diabetes, but its role in DR has not been directly studied. In Aim 2, we will elucidate the contribution of specific dopamine receptors on neuronal and vascular dysfunction in DR by testing the hypothesis that dopamine receptors selectively modulate neurons or vascular function such that dopamine receptor agonists will restore specific elements of DR dysfunction. To further establish the optimal treatment concentration for human clinical trials, in Aim 3 we will determine the most effective dosing for L-DOPA and dopamine receptor agonists in Type I and II DR by testing the hypothesis that L-DOPA and dopamine receptor agonists will provide benefit to Type I and II DR at much lower doses than used for other neurological conditions, avoiding potential side effects. These experiments are designed to establish whether dopamine-related treatments are protective for both neuronal and vascular defects in early and late DR, provide insights into the mechanisms by which neuronal and vascular defects occur, and determine the most effective dosing regimens for moving to human clinical trials. Our ultimate goal is to detect diabetic retinopathy at an early stage and then use the most efficacious dopaminergic agent to prevent vision loss and blindness in veterans with diabetes.